PROJECT SUMMARY (Project 1 - Hennig, Morris) Due to their relative chemical stability and ubiquity in the environment, chlorinated organic contaminants such as polychlorinated biphenyls (PCBs) continue to pose significant environmental public health risks. The toxic insult from these highly lipid-soluble toxic compounds is known to correlate with a range of post-exposure human health impacts, including endocrine disruption and vascular inflammation. In particular, coplanar PCBs, which act as an agonist of the aryl hydrocarbon receptor, have been shown to exert particularly toxic effects on the endothelium and associated vasculature. Atherosclerosis, a chronic inflammatory disease initiated by vascular endothelial cell dysfunction, remains the leading cause of death in the United States. Exposure to Superfund chemicals such as persistent chlorinated organic pollutants (e.g., PCBs) has been implicated as a risk factor for the development of atherosclerosis. Furthermore, PCB-induced toxicity has been linked to increased expression of caveolin-1, the major structural protein in caveolae membrane domains. Caveolae are particularly abundant in endothelial cells, where they are believed to play a major role in the regulation of endothelial vesicular trafficking and cell signal transduction. PCBs are also known to affect the cellular redox status, which may initiate antioxidant responses through nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling. Increasing evidence suggests that diets high in plant-derived bioactive food components (e.g., polyphenols) and omega-3 lipids are associated with a reduced risk of chronic inflammatory diseases such as atherosclerosis. Current data suggest that endothelial cell dysfunction and inflammatory events induced by exposure to coplanar PCBs can be markedly downregulated by polyphenols, such as flavonoids, as well as by omega-3 polyunsaturated fatty acids. Preliminary data suggest that caveolae and cytosolic Nrf2 signaling are sensitized by dietary omega-3 lipids and polyphenols. We propose three specific aims to test the hypotheses that: 1) PCB-induced endothelial toxicity and associated inflammatory events are regulated through the crosstalk between caveolae and Nrf2 related proteins such as Keap1; 2) dietary protective components, including polyphenols and omega-3 lipids, sensitize Nrf2 and caveolae signaling pathways, leading to a more effective anti-inflammatory cellular response against PCB insults; 3) dietary intervention in vivo can modify PCB-mediated initiation of inflammation and atherosclerosis through caveolae and/or Nrf2 signaling. Novel experimental methodologies including gene control constructs and bioanalytical technologies will be utilized to understand the interplay between Nrf2 and caveolae signaling. Results from our mechanistic studies will support the paradigm that healthful nutrition interventions may offer a powerful strategy to reduce disease risks associated with environmental toxic insults and to prevent inflammatory diseases, such as atherosclerosis, that have been linked to exposure to persistent chlorinated organic pollutants.